1. Field of the Invention
The invention relates to polycyclic guanine derivatives that can be useful as phosphodiesterase V inhibitors and/or for treating urological, vascular or pulmonary disorders.
2. Description
Phosphodiesterase (“PDE”) V inhibitor compounds inhibit the PDE V isoenzyme. Certain xanthine/guanine PDE V inhibitors are useful for treating cardiovascular and pulmonary disorders. For example, U.S. Pat. Nos. 5,824,683, 5,939,419 and 5,393,755, each incorporated herein by reference, disclose polycyclic guanine PDE V derivatives that are useful for the treatment of cardiovascular and pulmonary disorders.
Other PDE V inhibitors are useful for treating impotence. Erectile dysfunction or impotence is a treatable and highly recognized health concern, affecting more than 30 million men in the United States, including one in four over age 65. Erectile dysfunction occurs when a man consistently is unable to sustain an erection sufficient for conducting sexual intercourse. In the past, psychological reasons were the most common explanation for erectile dysfunction or it was considered a natural part of aging. Researchers today, however, acknowledge that more than 70 percent of instances of erectile dysfunction are due to physical or medical problems. There are several factors that may contribute to erectile dysfunction, including:                Poor blood circulation due to atherosclerosis or hardening of the arteries, high blood pressure and high cholesterol;        Neurological disorders such as multiple sclerosis, Alzheimer's disease or Parkinson's disease;        Hormone imbalances due to diabetes, thyroid disorders or low testosterone levels;        Trauma caused by spinal cord injury, prostate surgery or other trauma to the pelvic area;        Prescription and over-the-counter medications such as blood pressure medications, antidepressants or certain drug combinations; or        Lifestyle habits such as smoking, alcohol abuse or using illegal drugs.        
One group of PDE V inhibitors described by K. Murray in Phosphodiesterase VA Inhibitors, DN & P 6(3), 150-156 (April, 1993), (incorporated herein by reference) has potential therapeutic value for a number of physiological disorders. One compound disclosed in the Murray article is MIMAX, a polycyclic xanthine PDE V inhibitor substituted at its 8-position with a —NHCH3 group.
U.S. Pat. Nos. 5,409,934, 5,470,579, WO 93/23401, WO 92/05176 and WO 92/05175, each incorporated herein by reference, disclose certain xanthine PDE V inhibitors that are substituted at the 8-position with a number of different functionalities. Other heterocyclic PDE V inhibitors useful for treating impotence are disclosed in U.S. Pat. Nos. 6,140,329, 6,100,270 and WO 94/28902, each incorporated herein by reference.
The use of specific PDE V inhibitors for treating impotence has met with commercial success with the introduction of sildenafil citrate, a PDE V inhibitor commercially available as Viagra® (Pfizer, NY, N.Y.). The chemistry and use of Viagra®, including its mechanism of action in treating erectile dysfunction, are taught in EP 0 702 555 B1, incorporated herein by reference. Other PDE V inhibitors useful for treating erectile dysfunction are disclosed in WO 99/24433, incorporated herein by reference.
It would be desirable to provide a PDE V inhibitor that possesses beneficial therapeutic properties, useful pharmacological properties and good metabolic stability. It would further be desirable to provide a PDE V inhibitor that is highly potent and selective over other types of PDE inhibitors, and is effective for treating a variety of physiological symptoms and diseases in which PDE V plays a role, especially a treatment for erectile dysfunction with minimal side effects.